Abstract As humans live longer, age-related neurodegenerative disorders caused by the accumulation of abnormal proteins are becoming increasingly common. In all cells, a protein quality control network (PQC) exists to handle such abnormal proteins arising from mutations, environmental stressors or the aging process. The selective brain vulnerability in age-related neurodegenerative disorders, however, suggests there is something unique about PQC in the brain that makes this organ particularly susceptible to misfolded proteins. Unfortunately, which PQC components are most important in the brain and how these components respond when exposed to abnormal proteins remain unknown. The studies proposed here will systematically explore changes in PQC that occur when aggregation-prone proteins are expressed in brain and will define mechanistically how a key PQC ubiquitin ligase, CHIP, handles neurodegenerative disease proteins. The underlying hypothesis is twofold: 1) PQC in the brain fails to keep pace with mounting proteotoxic stress during age-related neurodegeneration; and 2) the brain's PQC response to proteotoxic stress relies heavily on CHIP, a multifunctional protein that mediates crosstalk between chaperone- and ubiquitin-dependent pathways. In three Aims that build off the investigators' expertise in polyglutamine neurodegeneration and ubiquitin ligase biology, we will use complementary genetic and biochemical techniques to map basal and adaptive PQC changes in the aging mouse brain and in mouse models of polyglutamine neurodegenerative disease, both in the presence and absence of CHIP. Additional studies will determine the mechanisms by which CHIP ligase complexes are regulated in brain. The proposed studies will identify key PQC components that act on abnormally folded protein in the CNS and provide insights into their mechanisms of action. The results are expected to suggest targets for therapeutic strategies in a wide range of age-related neurodegenerative disorders.